Environmental Enteric Dysfunction (EED) was first described as a malabsorption syndrome with small intestinal villous flattening among healthy adults in Thailand and other low-resource settings.1–4 A similar entity was described in Peace Corps volunteers in South Asia.5,6 Several years later, resolution of histopathology and malabsorption after repatriation or immigration to North America was demonstrated.7,8
Ensuing studies described that a similar entity, also manifested by abnormal histopathology, permeability defects, inflammation, and impaired nutrient absorption, is widespread among impoverished children in settings with poor sanitation and hygiene.9–14 Recent data corroborate these findings, and associate increased gut permeability and inflammation with ponderal, and especially linear, growth faltering in children living in low-income countries.15–19 Such growth deficits have been associated with poor outcomes such as cognitive delay and chronic noncommunicable diseases in adulthood.20–22 Although the precise cause(s) of EED remain(s) elusive, exposure to fecally contaminated environments, specific microbes, and/or a paucity of beneficial intestinal bacteria are candidate precipitants.19,23
Recent and ongoing studies are assessing relationships between intestinal dysfunction and suboptimal growth in childhood. The Malnutrition and Enteric Diseases (MAL-ED) Network demonstrated that intestinal permeability defects were common among young children in Asia, Africa, and Latin America.24 The EED Biomarkers Initiative Consortium is identifying and validating candidate biomarkers and increasing our understanding of EED pathophysiology.25 Water, sanitation and hygiene (WaSH) trials are testing effects of environmental interventions on EED prevalence.26,27
However, even if WaSH efficacy trials demonstrate the ability of these interventions to reduce EED burden, this entity is unlikely to be eliminated soon, as efforts to implement WaSH at high coverage have been inadequate. For example, at least 1.8 billion people worldwide are estimated to drink fecally contaminated water, and only 68% have access to “improved” sanitation facilities, as defined by the United Nations Joint Monitoring Program.28 Also, the capacity to implement hygiene practices is constrained because of insufficient access to water of any quality. Hence, even if WaSH can prevent EED, many children will continue to suffer from EED and its consequences, and substantial interest exists in identifying and trialing therapeutics.29
Given its obscure etiology, largely sub-clinical nature, and no clear role for a single biomarker to identify a case, it is currently impossible to diagnose a specific child with EED. This uncertainty has impeded the design of clinical trials for this important entity. Recently, Keusch et al.30 introduced a paradigm shift toward functional gastrointestinal deficit as a defining feature of EED, but acknowledged the challenges in formulating a well-circumscribed, clinically and epidemiologically useful, durable definition. Thus, a formal case definition of EED will constitute a significant advance in the study of therapeutic interventions.
Therapeutics trials necessarily use more cautious case definitions than those used in prevention studies, which generally recruit community-based asymptomatic/presymptomatic individuals and test interventions with little or no risk (e.g., WaSH interventions). Therapeutics pose risks that are at least hypothetically greater than those tested in prevention studies. An EED case definition within the context of therapeutic trials, should, therefore be sufficiently specific to exclude individuals unlikely to have EED, to minimize potential harm, and maximize possible benefit. Such specificity also reduces potential misclassification and false ascertainment of lack of efficacy, as the likelihood of identifying a true effect diminishes because of misclassification (i.e., type 2 error).31 In other words, if children do not “respond” because they do not have the condition, a null finding is more likely, thereby leading to potentially dismissing a treatment that might work.
To advance the EED field, we now propose a definition construct analogous to the Jones criteria for acute rheumatic fever, intended for therapeutic trials, and which can be modified as new data emerge. In building this proposal, we recognize that EED is, except for poor growth, rarely accompanied by clinical signs or symptoms, so our criteria highly depend on laboratory assessment. Accordingly, our definition is based on three domains, which, taken together, indicate an acquired intestinal inflammatory disorder with substantial clinical impact. Domain 1 includes age, presence of linear growth failure, negative celiac disease testing; domain 2 includes gut histopathology consistent with EED or at least two intestinal deficits assessed by less invasive biomarkers; domain 3 consists of biomarkers nonspecific to enteric dysfunction, but representing consequences of EED. We discuss a “sliding scale” application of the proposed criteria based on the adverse event potential of the therapy. Finally, we propose a definition of response to intervention.
We acknowledge Parminder Suchdev for his guidance on defining linear growth faltering, David Rudnick for his thoughtful review of our manuscript and Hannah Atlas for manuscript preparation.
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